Peutz-Jeghers Syndrome

Overview

Definition

Peutz-Jeghers syndrome (PJS) is an autosomal-dominant inherited disorder defined by intestinal, hamartomatous polyps, and skin/mucosal melanin macules.

Epidemiology

• Relatively rare
• 1 case per 60,000–300,000
• Median age for 1st presentation of polyps: 11–13 years old
• Approximately 50% of people have symptoms by age 20.
• 50%–80% of STK11 mutations are familial.
• Both sexes are equally affected.
• Cancer risk ↑ with age: 
  • 1%–2% risk by 20 years old
  • Approximately 30% by 50 years old
  • Approximately 80% by 70 years old
• 15x ↑ risk of developing intestinal cancer

Etiology

• Autosomal-dominant inherited-germline mutation of the serine/threonine kinase 11 (STK11/LBT1) tumor-suppressor gene on chromosome 19p13
• STK11 mutation: associated with 90% of PJS cases

Pathophysiology

• Functions of tumor-suppression and cell-cycle regulation of the STK11/LKB1 gene are compromised.
• Encodes for multifunctional serine/threonine kinase (STK), which is important in 2nd-messenger signal transduction
• STK modulation:
  • Cellular proliferation
  • Cell polarity
  • Important role in responding to ↓ cellular energy levels
• STK11 protein → inhibition of AMP-activated protein kinase (AMPK) → signals the inhibition of the mechanistic target of rapamycin kinase (mTOR)
• In PJS, the mTOR pathway is dysregulated.
• Polyps are caused by an overgrowth of cells native to the normally occuring area. 
• Initially, polyps have no presumed neoplastic potential.
• Hamartomatous polyps are made of:
  • Normal cellular elements of the GI tract
  • Microscopically distorted architecture:
    • Extensive smooth-muscle proliferation
    • Elongated, arborized pattern of polyp formation
• PJS polyps are differentiated from other hamartomatous polyps by a unique, smooth-muscle core arborizing throughout the polyp.

Clinical Presentation

History

• Parents may report perioral and buccal macules, which 1st appear around 5 years of age.
• Family history of PJS
• During the 1st 3 decades of life:
  • Anemia
  • Rectal bleeding
  • Abdominal pain
  • Obstruction
  • Intussusception

Physical examination

• Mucocutaneous pigment and melanin macules in lips, perioral area, buccal mucosa, eyes, nostrils, fingertips, palms, soles, and perianal areas:
  • 1–5 mm macules
  • Present in more than 95% of cases
  • Small, flat, brown, or dark-blue spots
  • Similar in appearance to freckles
  • Most commonly around the:
    • Mouth crossing the vermilion border: 94%
    • Nostrils
    • Perianal area
    • Digits
    • Dorsal and volar aspects of hands and feet: 62%–74%
  • May fade after puberty, but tend to persist in the buccal mucosa
• Rectal polyps may be found during a rectal examination.
• Gynecomastia and growth acceleration (due to Sertoli-cell tumor)
• Testicular mass

Diagnosis

• World Health Organization diagnostic criteria include any of the following:
  • > 3 PJS polyps on histology
  • Any number of PJS polyps + family history of PJS
  • Characteristic mucocutaneous pigmentation + family history of PJS
  • Any number of PJS polyps + characteristic mucocutaneous pigmentation
• PJS polyps do not have specific features on endoscopy and can only be reliably distinguished from other types of polyps by histopathology. 
• Genetic testing can be used for confirmation of PJS:
  • Variable sensitivity of the test
  • Familial cases: 70%
  • Sporadic cases: 30%–67%

Management

Observation

• Extend genetic counseling to patients and their families (especially patients wishing to have children).
• Endoscopy: 
  • Beginning at 12 years old, repeating every 2–3 years into adulthood
  • If polyps are found, repeat annually.
• Colonoscopy: 
  • Beginning at 12 years old, repeating every 1–3 years (earlier if symptomatic)
  • If polyps are found, repeat annually.
• MRCP: 
  • Beginning at 25–30 years old, repeating every 1–2 years
• Breast-cancer screening:
  • Clinical examination: beginning at 25 years old, repeating every 6 months
  • Mammogram: beginning at 25 years old
• Papanicolaou smear: annually
• Transvaginal ultrasound: beginning at 18 years old, repeating annually
• Testicular examination: beginning at 10 years old, repeating annually

Surgical management

• Endoscopic polypectomy for polyps > 0.3 cm
• Prophylactic mastectomy 
• Prophylactic hysterectomy and bilateral salpingo-oophorectomy after completion of childbearing
• Other surgeries include laparotomies and laparoscopies for GI involvement and extraintestinal complications. 
• Laparotomy and resection may be necessary for intussusception, obstruction, or persistent intestinal bleeding. 

Prognosis

• 39% lifetime risk of colorectal cancer
• 32%–54% lifetime risk of breast cancer
• Approximately 50% of patients with PJS die from cancer by 57 years old.
• Mean age of 1st cancer diagnosis: 43 years old

Complications

• Intussusception in 69% of patients
• GI obstruction by polyps in the small and large bowel in 43% of patients
• Mesenteric ischemia in 23% of patients
• Iron-deficiency anemia
• GI bleeding from ulcerations in 14% of patients
• Extrusion of polyp in 7% of patients

Differential Diagnosis

• Cowden disease: an autosomal-dominant disorder caused by mutations in PTEN, a tumor-suppressor gene. Cowden disease is a genodermatosis and characterized by multiple, benign hamartomas (in any location), mucocutaneous lesions, and macrocephaly. Management depends on the location of the hamartoma. 
• Hereditary nonpolyposis colon cancer (HNPCC): an autosomal-dominant disorder caused by mutations in the mismatch repair (MMR) genes, leading to the development of colorectal cancer in 1st-degree relatives. Hereditary nonpolyposis colon cancer is also known as Lynch syndrome. Management is with prophylactic colectomy and frequent endoscopy for surveillance. 
• Juvenile polyposis: an autosomal-dominant condition characterized by the growth of hyperplastic, hamartomatous polyps in the colon. Juvenile polyposis is commonly associated with mutations in the SMAD4 and BMPR1A genes. Diagnosis is made by visualization of > 5 polyps on colonoscopy, or any number of polyps + a positive family history. Management is surgical to reduce the likelihood of GI bleeding and obstruction. 
• Colorectal cancer (CRC): the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease, arising from genetic and epigenetic abnormalities, with influence from environmental factors. Almost all cases of CRC are adenocarcinoma. Because most cases are asymptomatic, screening is important. Diagnosis is by colonoscopy and management is primarily surgical.
• Thyroid cancer: malignancy of the thyroid-gland cells arising from thyroid follicular cells or calcitonin-producing C cells. Papillary cancer is the most common type associated with familial adenomatous polyposis (FAP). Exposure to ionizing radiation and iodine deficiency are also risk factors. Diagnosis is with thyroid-stimulating hormone, ultrasound, and biopsy. Management is mainly surgical.